The goal of this project is to assess the role of immunological and genetic factors in the etiology of autoimmune diseases of the nervous system. Particular emphasis is placed on studies of multiple sclerosis (MS) which is thought to have an autoimmune basis. In addition, HTLV-I- associated myelopathy/tropical spastic paraparesis (HAM/TSP) is studied as a possible example of viral-induced immunopathological disease. Studies of MS have focused on achieving a better understanding of T cell recognition of putative antigens such as myelin basic protein (MBP). Understanding of the interactions between presentation of antigen by HLA molecules and recognition of the HLA/antigen complex by the T cell receptor, known as the trimolecular complex, have advanced significantly. The immunodominant portion of MBP have been found to be related to peptide binding to the DRB1*1501 and DRB5*0101 molecules. These molecules represent the HLA genes most commonly associated with MS. Identification of portions of the immunodominant region of MBP have identified alterations that can be made in the peptide which will allow binding to the HLA molecule but alter the T cell response to the molecule. This approach, the use of an altered peptide ligand, is now nearing testing as a therapeutic approach in MS. Results from this type of clinical trial should help to define the role of MBP as a target antigen in MS. Studies of HAM/TSP have shown that one portion of the virus, the tax peptide, is most commonly recognized by patients who are seropositive for the HTLV-I virus and who are symptomatic with neurological disease. This portion of the virus seems to be preferentially presented by HLA-A2 and a high frequency of HLA class I- restricted T cells that are found in the disease. These T cells may contribute to the disease process. Currently, a treatment trial using a monoclonal antibody that is specific for the IL2 receptor, a marker for activated T cells, is being tested as a potential means of reducing the frequency of HTLV-I-specific T cells and modifying disease. Thus, the understanding of the immunological and genetic factors involved in diseases such as MS and HAM/TSP should lead to rational approaches to therapy.